Definition
- Errors in the establishment of chromosomal, gonadal, or phenotypic sex cause abnormal sexual differentiation.
- Variety of patterns from ambiguous genitalia to apparently normal genitalia with sterility.
Pathophysiology
- Sexual differentiation is a sequential process-chromosomal sex established at fertilization (dog: 78,XX or 78,XY; cat: 38,XX or 38,XY), development of gonadal sex, and finally development of phenotypic sex.
- Testis differentiation normally determined by sex chromosome constitution; SRY (on the Y chromosome) and SOX9 (autosomal gene), expressed by Sertoli cells, are critical for testis differentiation.
- Ovarian differentiation-an active process involving WNT4/RSPO1 and
-catenin. - Phenotypic sex differentiation (tubular reproductive tract and external genitalia) depends on gonadal sex-basic embryonic plan is female; male phenotype results if testes are capable of secreting MIS and testosterone at the correct time during embryogenesis, and functional androgen receptors (X-linked gene) are present on genital tissues.
- Consensus terminology for categorizing Disorders of Sexual Development recently revised. Previous nomenclature also noted.
Sex Chromosome DSD
- Defects in number or structure of sex chromosomes-chromosomal non-disjunction during meiosis causes trisomy, monosomy; mitotic non-disjunction of a single zygote causes mosaicism; fusion of zygotes leads to chimerism.
- XXY (Klinefelter) syndrome-79,XXY (dog); 39,XXY (cat); hypoplastic testes; phenotypic male (normal to hypoplastic genitalia); sterile; some tortoiseshell male cats.
- XO (Turner) syndrome-77,XO (dog); 37,XO (cat); dysgenetic ovaries; phenotypic female; infantile genitalia; sterile.
- XXX syndrome-79,XXX (dog); hypoplastic ovaries anestrus to irregular estrous cycles; female phenotype; high FSH and LH; somatic abnormalities common in XXX women.
- True hermaphrodite chimera-XX/XY or XX/XXY; ovarian and testicular tissue; phenotypic sex depends on amount of testicular tissue; dogs and cats.
- XX/XY chimera with testes and XY/XY chimera with testes-vary from phenotypic female with abnormal genitalia to male with possible fertility; dogs and cats (some tortoiseshell males).
XY DSD
Disorders of Testicular Development
- Complete or partial testicular dysgenesis-SRY-positive 78,XY dog; genitalia incompletely-masculinized: (enlarged clitoris); testes undescended or perivulvar; Müllerian and Wolffian duct derivatives variably present.
- Ovotesticular DSD-(XY sex reversal, true hermaphrodite)
- SRY-positive 38,XY true hermaphrodite cat (one report); ovotestes in ovarian position; Müllerian and Wolffian duct derivatives present; penis
- 78,XY (SRY status unknown) dog; ambiguous female genitalia (enlarged clitoris, os clitoris); abdominal ovary (hypoplastic) and testis (Sertoli cell tumor, no spermatogenesis).
Disorders in Androgen Synthesis or Action
- Complete androgen insensitivity syndrome-38,XY cat; testes at caudal pole of kidneys; no Wolffian or Müllerian duct derivatives; blind-ended vagina; vulva.
- Partial androgen insensitivity syndrome-78,XY dog; vulva; perivulvar scrotal-like swellings at 6 months of age; blind vaginal pouch; hypoplastic testes; epididymides, partially developed vasa deferentia; vulvar fibroblasts unable to bind dihydrotestosterone.
- Persistent Müllerian duct syndrome (male pseudohermaphrodite)-XY; testes (50% are unilateral or bilateral cryptorchid); epididymides, vasa deferentia, prostate, oviducts, uterus, cervix, cranial vagina; penis, prepuce, and scrotum usually normal; dogs and cats.
- Isolated hypospadias-incomplete masculinization of urogenital sinus during urethral development causing abnormal location of urinary orifice from glans penis (mild) to perineum (severe); external genitalia unambiguous; testes (cryptorchid or scrotal) or bifid scrotum (cats) with spermatogenesis.
XX DSD
Ovoteseticular DSD and Testicular DSD
- Canine XX DSD (sex reversal)-SRY-negative 78,XX reported in 28 dog breeds, not in cats; the autosomal gene causing testis induction presently unknown; not due to mutation of genes involved with sex reversal in polled goats and humans; two phenotypes:
- Ovotesticular DSD, XX true hermaphrodite (90% of cases)-ovotestis (at least one); masculinized female phenotype; varies from normal to abnormal vulva, normal or enlarged clitoris (os clitoris possible), uterus, oviducts, epididymides, and vasa deferentia; rarely fertile
- Testicular DSD, XX males (10% of cases)-testes (usually cryptorchid); epididymides, vasa deferentia, prostate; bicornuate uterus, no oviducts; hypoplastic penis and prepuce; hypospadias common.
Androgen Excess
- Fetal origin-single report of congenital adrenal hyperplasia in a phenotypic male cat (38,XX, ovaries, oviducts, epididymides, vasa deferentia, bicornuate uterus); due to 11 -hydroxylase deficiency; ACTH, testosterone, progesterone, 17-OH-progesterone, androstenedione, deoxycorticosterone, 11-dexoycorticosterone elevated.
- Maternal origin (female pseudohermaphrodite)-XX; ovaries; masculinized genitalia (mild clitoral enlargement to nearly normal male genitalia); oviducts, uterus, cranial vagina; prostate variable; caused by sex steroid administration during pregnancy; rare in dogs and cats.
Systems Affected
- Reproductive-anomalies of the gonads, tubular tract, and external genitalia.
- Renal/Urologic-occasionally affected (e.g., agenesis, incontinence, hematuria, cystitis).
- Skin/Exocrine-perivulvar dermatitis (hypoplastic vulva); perineal or peri-preputial dermatitis (hypospadias); hyperpigmentation (Sertoli cell tumor).
Genetics
- Chromosomal sex abnormalities-usually caused by random events during gamete formation or early embryonic development.
- XX DSD-autosomal recessive trait in American cocker spaniels and likely in beagles, German shorthaired pointers; familial in English cocker spaniels, Chinese pugs, Kerry blue terriers, Norwegian elkhounds, Weimaraners; other reported breeds include soft-coated Wheaten terriers, vizslas, Walker hounds, Doberman pinschers, basset hounds, American pit bull terriers, border collies, Afghan hounds.
- PMDS-autosomal recessive trait in miniature schnauzers in the US, Basset hounds in the Netherlands, and possibly Persian cats; expression limited to XY individuals.
- Hypospadias familial in Boston terriers.
- Failure of androgen-dependent masculinization (predominantly cats) probably X-linked.
Incidence/Prevalence
- Generally rare.
- In affected breeds-may be common within families or within the breed as a whole.
Signalment
Species
Dog and cat
Breed Predilections
Dogs (see “Genetics”).
Mean Age and Range
All are congenital disorders, but individuals with normal external genitalia may not be identified until breeding age or at routine gonadectomy.
Predominant Sex
Phenotypic females and males
Signs
General Comments
- Depends on type of disorder.
- Listed are possible findings for any of the conditions; not all occur with each specific disorder.
Historical Findings
- Failure to cycle.
- Infertility and sterility.
- Vulva, clitoris, prepuce, or penis-abnormal size, shape, or location.
- Urine stream-abnormal location.
- Affected phenotypic males attractive to other males.
- Urinary incontinence.
- Vulvar discharge.
- PU/PD.
Physical Examination Findings
- Vulva normal or hypoplastic.
- Clitoris normal or enlarged; os clitoris.
- Perivulvar dermatitis and vulvar discharge.
- Testes scrotal, unilateral or bilateral cryptorchid; bifid scrotum.
- Penis and prepuce normal or hypoplastic.
- Urethral meatus normal or abnormal location.
- Dermatologic signs of hyperestrogenism in males.
- Abdominal mass.
Causes
- Congenital-heritable or non-heritable
- Exogenous steroid hormone administration during gestation
Risk Factors
Androgen or progestagen administration during pregnancy (female pseudohermaphrodite).
